Ibrutinib is an organic small molecule having IUPAC name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one. It is described in a number of published documents, including international patent application WO 2008/039218 (Example 1b), and is described as an irreversible inhibitor of Btk.
Btk plays an essential role in the B-cell signaling pathway linking cell surface B-cell receptor stimulation to downstream intracellular responses. Btk is a key regulator of B-cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). In addition, Btk plays a role in a number of other hematopoetic cell signaling pathways, e.g. Toll like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in Mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. See e.g., C. A. Jeffries, et al., (2003), Journal of Biological Chemistry 278:26258-26264; N. J. Horwood, et al., (2003), The Journal of Experimental Medicine 197:1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3):1646-1656, and Quek et al (1998), Current Biology 8(20):1137-1140.
Ibrutinib is therefore being studied in Phase II and III clinical trials for various hematological malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma and multiple myeloma.
There are various processes for preparing functionalised bicyclic heterocycles, for example as described in US patent document US 2011/0082137, which includes syntheses to fused bicycles from pyrazoles and substituted hydrazines.
Ibrutinib may be prepared in WO 2008/039218 (Example 1b) in accordance with the following scheme:

First, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine may be prepared in accordance with procedures described in WO 2008/039218, for instance by converting 4-phenoxybenzoic acid to the corresponding acyl chloride (by using thionyl chloride), which latter product may be reacted with malononitrile to prepare 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene. The methoxy moiety is then methylated using trimethylsilyldiazomethane, and that methylated product is the treated with hydrazine hydrate to provide 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole, which is reacted with formamide to provide 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine, as illustrated in the following scheme:

Thereafter, the 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine may have the requisite piperidinyl moiety introduced at the 1H-position (i.e. on the —NH of the pyrazole moiety). As indicated in the above scheme, this is done by means of a Mitsunobu reaction—more specifically by converting the hydroxy moiety of the Boc-protected 3-hydroxypiperidine-1-carboxylate to a better leaving group, thereby allowing a substitution reaction with the —NH moiety of the pyrazole (with inversion). Hence, the chirality of the hydroxypiperidine is translated into the product, which is then converted to the single enantiomer ibrutinib by Boc-deprotection and acylation with acryl chloride.
This process has a number of disadvantages, such as those associated with cost, efficiency and environmental disadvantages. For instance the Mitsunobu step may be wasteful, costly and cumbersome. It is therefore desired to find a new process that overcomes these disadvantages.
There is now provided a process for the preparation of a compound of formula I,

or a derivative thereof, wherein
R1 represents a nitrogen protecting group;
R1a represents —CN, —C(O)OR1b or —C(O)N(R1c)(R1d);
R1b, R1c and R1d each independently represent C1-6 alkyl, aryl or heteroaryl;
R2a represents:                (i) phenyl substituted at the 4-position with halo or —O—R2b; or        (ii) hydrogen;        
R2b represents hydrogen or phenyl;
which process comprises reaction of a compound of formula II,

or a derivative thereof, wherein
R1a and R2a are as defined above;
X1 represents a suitable leaving group,
with a compound of formula III,

or a derivative thereof, wherein R1 is as defined above,
which process is hereinafter referred to as a “process of the invention”.
In the processes of the invention described herein, it is indicated that “derivatives” may be employed, which includes salts and solvates. Hence, for instance the compound of formula (III), i.e. the hydrazine, may be in the form of the free base or in the form of a salt (e.g. a di-hydrogen chloride salt, although the hydrazine may be in another salt form). Where appropriate, “derivative” may also encompass a relevant protecting group (which may be removed later in the synthesis scheme). It should also be noted that compounds mentioned herein may exhibit isomerism, e.g. tautomerism.
It is further indicated above that R1 is a nitrogen protecting group. Such groups include those that result in the formation of:                an amide (e.g. N-acetyl)        optionally substituted N-alkyl (e.g. N-allyl or optionally substituted N-benzyl)        N-sulfonyl (e.g. optionally substituted N-benzenesulfonyl)        a carbamate        a urea        trityl (triphenylmethyl), diphenylmethyl, or the like        
Hence, R1 may, amongst other groups, represent:
—C(O)Rt1 (in which Rt1 preferably represents C1-6 alkyl or optionally substituted aryl);
C1-6 alkyl, which alkyl group is optionally substituted by one or more substituents selected from optionally substituted aryl (e.g. preferably forming a benzyl moiety);
—S(O)2Rt2 (in which Rt2 preferably represents optionally substituted aryl); or, preferably, —C(O)ORt3 (in which Rt3 preferably represents optionally substituted aryl or, more preferably, optionally substituted C1-6 (e.g. C1-4 alkyl, e.g. tert-butyl (so forming, for example, a tert-butoxycarbonyl protecting group, i.e. when taken together with the amino moiety, a tert-butylcarbamate group) or a —CH2phenyl group (so forming a carboxybenzyl protecting group);
—C(O)N(Rt4)Rt5 (in which, preferably, Rt4 and Rt5 independently represent hydrogen, C1-6 alkyl, optionally substituted aryl or —C(O) Rt6, and Rt6 represents C1-6 alkyl or optionally substituted aryl).
Unless otherwise specified, alkyl groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain, and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl groups may also be part cyclic/acyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated.
The term “aryl”, when used herein, includes C6-10 groups. Such groups may be monocyclic, bicyclic or tricyclic and, when polycyclic, be either wholly or partly aromatic. C6-10 aryl groups that may be mentioned include phenyl, naphthyl, and the like. For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.
The term “heteroaryl”, when used herein, includes 5- to 14-membered heteroaryl groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur. Such heteroaryl group may comprise one, two or three rings, of which at least one is aromatic. Preferably, such groups are 5- to 12-membered, e.g. 5- to 10-membered.
Where mentioned herein, C1-6 alkyl, aryl and heteroaryl may be optionally substituted. Such substitution is possible if it does not affect the concept of the invention, i.e. the process(es) defined herein (which may be performed on certain compounds irrespective of the substitution pattern thereon). Such substituents include aryl (e.g. phenyl, itself optionally substituted by substituents selected from halo, alkyl and the like), alkyl, halo, —CN and the like.
It is indicated that X1 represents a suitable leaving group, and in particular may represent chloro, bromo, iodo, —OR3a (in which R3a represents optionally substituted alkyl, e.g. in which the optional substituent(s) include aryl such as phenyl, so forming e.g. —OCH3, —OCH2-phenyl or the like) or a sulfonate group (e.g. —O—S(O)2R4a, in which R4a represents optionally substituted alkyl or aryl, so forming e.g. —OS(O)2CF3, —OS(O)2CH3 or —S(O)2PhMe or the like, i.e. tosyl, mesyl or the like).
Preferred compounds of formula (I) that may be prepared by a process of the invention described herein include those in which:
R1a represents —CN;
R2a represents phenyl substituted at the 4-position by —O—R2b; and/or
R2b represents phenyl;
hence the compound of formula (I) is preferably:

the compound of formula (II) is preferably:

wherein, preferably, X1 represents —OR3a, in which R3a is preferably alkyl, more preferably unsubstituted alkyl and, most preferably, methyl, so forming a —OCH3 group;
and hence, most preferably, the compound of formula (II) represents:

For the avoidance of doubt, the compound of formula (III) is a single enantiomer containing a chiral centre that has an (R)-configuration. By single enantiomer, we mean that the compound is present in some enantiomeric excess (in this case, that there is more (R)-enantiomer present than the (S)-enantiomer), for instance in greater than 50% ee, e.g. greater than 60% ee. The chirality is retained in the process of the reaction, i.e. the reaction is stereospecific, and the compound of formula (I) thereby produced is also a single enantiomer with the same configuration at the relevant chiral centre. Downstream synthetic steps will also proceed with retention of the stereochemistry (unless specified otherwise).
Particularly preferred protecting groups that R1 may represent include those forming carbamates (especially the tert-butoxycarbonyl or t-Boc group and the carboxybenzyl or Cbz group) and substituted alkyl moieties (especially the benzyl group). Such protecting groups may be more easily introduced onto the compound of formula (III) and/or ultimately more easily removed from the relevant nitrogen atom in a downstream step.
Such a process of the invention may be conducted using the free base of a compound of formula (III) or salt thereof, e.g. a di-hydrogen chloride salt of the compound of formula (III). Further the protecting group R1 is preferably a non acid-labile protecting group (e.g. a group labile to base or removable though hydrogenation or the like) such as a carboxybenzyl (Cbz) protecting group. However, the choice of this protecting group is influenced by the choice of the protecting group R2 (e.g. the two are preferably mutually compatible) as indicated hereinafter.
In this aspect of the process of the invention, the compound of formula (III) (or derivative thereof, e.g. di-HCl salt) may be added to the compounds of formula (II). Preferably less than two equivalents of the compound of formula (III) is employed compared to the compound of formula (II), more preferably less than 1.5 equivalents. However, the equivalents ratio of compound of formula (III) to compound of formula (II) may be between 1.5:1 to 1:1.5, preferably between 1.2:1 to 1:1.2 and in particular, the ratio is about 1:1.
Preferably, this aspect of the process of the invention may be performed in a suitable solvent, such as in the presence of a polar solvent, such as an alcoholic solvent (e.g. ethanol) and/or water, or mixtures thereof. It is preferred that a mixture of an alcohol (e.g. ethanol) and water is employed. Compared to the weight of the compound of formula (II) employed, at least one (e.g. at least five, but preferably less than 20) volume equivalent(s) of the solvent/alcohol and at least one (e.g. at least five, but preferably less than 20) volume equivalents of water are employed. Preferably about 13 volume equivalents of the alcohol and about 10 volume equivalents of water are employed.
Preferably, the compound of formula (II) in the presence of a suitable solvent (as described above) is cooled to below room temperature, for example to below 10° C., e.g. to about 5° C. The compound of formula (III) (or derivative thereof) is then added to the mixture of compound of formula (II) and solvent. Preferably this is done so as to maintain the temperature of the reaction mixture below room temperature (e.g. at below about 10° C., preferably between 5 and 10° C.). For instance, this addition may be drop-wise.
This process aspect of the invention is preferably conducted in the presence of a base, such as an organic base, preferably an amine base such as a tertiary amine base (e.g. triethylamine). Preferably between one and four molar equivalents of base are employed in the process of the invention (compared to the molar equivalents of the compound of formula (II) or (III)), and more preferably between 1.5 and 2.5 equivalents are employed (e.g. about two equivalents). Preferably the base is added dropwise, and preferably the temperature is maintained at below room temperature (e.g. at below about 10° C., preferably between 5 and 10° C.).
After the addition of the base, the reaction mixture is the preferably allowed to warm to about room temperature, after which it is allowed to stir at that temperature for a period of time (during which the conversion to desired product compound (I) may be monitored), which may depend on the conversion rate to product. Typically, the reaction mixture is allowed to stir for at least 20 minutes, for example for about one hour, after which further water may be added (e.g. between about 10 and 20 volume equivalents), the reaction mixture may be cooled (again) to below room temperature (e.g. to below about 10° C., preferably about 5° C. or below, e.g. about 0° C.). The desired product may then solidify, and may therefore be separated/isolated by filtration. It may be further purified if required.
Such an aspect of the process of the invention has several advantages. For instance, the fact that the substituted hydrazine of formula (III) (that may be employed in e.g. the free base form, or in the salt form which may be formed in situ) is employed in the reaction has at least the following advantages:                (i) the use of hydrazine hydrate is avoided, which is a hazardous reagent to handle, especially at high temperatures (for instance hydrazine is combustible even in the absence of oxygen);        (ii) the reaction leads to a 1N-substituted pyrazole and hence downstream substitution at the 1N-position is circumvented (when substitution is required at that position), for instance a downstream Mitsunobu reaction to introduce a substituent is circumvented, the latter reaction generating enormous amounts of waste (e.g. the Mitsunobu reaction may require two equivalents of the 3-hydroxy-N-Boc piperidine, due to a competing elimination reaction);        (iii) the use of the expensive chiral 3-hydroxy-N-Boc piperidine is circumvented;        (iv) the reaction of compound (II) with a non-symmetrical hydrazine may be expected to result in a variety of products (as opposed to reaction with the symmetrical hydrazine itself) but however, advantageously and unexpectedly, the reaction proceeds in a regioselective manner. That is the process of the invention predominantly results in the formation of a pyrazole with a substitution pattern as depicted by the compound of formula (I), i.e. in the 1(N)-position the piperidine, R2a group (e.g. 4-phenoxy-phenyl) in the 3-position, etc, as opposed to a pyrazole with the piperidine at the 2-position adjacent the R2a group. Advantageously, the desired regioisomer is present in higher quantity than the undesired regioisomer, and for instance is present in a ratio of greater than 75:25 compared to the undesired regioisomer, more particularly, this ratio is greater than 90:10, and most advantageously there may be a negligible or undetectable amount of the undesired regioisomer.        
Hence, this aspect of the process of the invention may be advantageous in terms of economy (e.g. cost of goods), efficiency and environmental considerations (e.g. less waste).
After the first process of the invention, the compound of formula (I) that is prepared may be converted to a compound of formula (IV),

or a derivative (including isomer) thereof, wherein R1 is as hereinbefore defined.
In the conversion to the compound of formula (IV), the compound of formula (I) may first be converted to a compound of formula (IVA),

or a derivative (including isomer), wherein X2 represent —OH or —NH2, and R1 and R2a are as hereinbefore defined.
For instance, for compounds of formula (I) in which R1a represents —CN, a corresponding product of formula (IVA) in which X2 represents —NH2 may be produced by reaction with either:                (i) formamide (HCONH2);        (ii) formamidine or a formamidine salt H—C(═NH)—NH3+X−, wherein X− represents a suitable counterion, such as a halide (e.g. Cl−) or an oxy anion (e.g. acyl-O−), so forming for example formamidine HCl or formamidine acetate or the like;        (iii) alkyl (e.g. ethyl) formimidate, or a salt thereof, such as ethyl formimidate HCl;        (iv) ethylorthoformate followed by ammonium acetate.        
For compounds of formula (I) in which R1a represents —C(O)OR1b or —C(O)N(R1c)(R1d), a corresponding product of formula (IVA) in which X2 represents —OH (or a tautomer thereof, as depicted by formula (IVB) below) may be produced by reaction with for example, CH(OEt)3 optionally in the presence of a catalyst (e.g. ZnCl2, 0.1 equiv), followed by the addition of e.g. NH4OAc, which reaction may be performed in the presence of a suitable solvent (e.g. an aromatic solvent such as toluene):

Thereafter, compounds of formula (IVA) in which X2 represents —OH (or the tautomer, i.e. compound (IVB) depicted above) may be converted to corresponding compounds of formula (IVA) in which X2 represents —NH2, by first converting to the corresponding chlorinated derivative (which need not be isolated) followed by a nucelophilic aromatic substitution to provide the desired compound, conditions including the use of POCl3 (or another suitable chlorinating reagent) followed by reaction with NH4OAc (or another suitable source of ammonia).
For compounds of formula (IVA) in which R2a represents hydrogen, such a compound may be converted to a compound of formula (IVC):

wherein X2 is as hereinbefore defined, and X3 is a suitable group such as halo (e.g. bromo, chloro or preferably, iodo), which reaction may take place in the presence of a source of halide, for instance an electrophile that provides a source of iodine includes iodine, diiodoethane, or preferably, N-iodosuccinimide, and sources of bromide and chloride include N-bromosuccinimide and N-chlorosuccinimide, and which reaction may be performed in the presence of a suitable solvent such as an alcohol (e.g. methanol) or preferably a halogenated solvent (e.g. chloroform) or a polar aprotic solvent (such as DMF).
Compounds of formula (IVC), in particular those in which X2 represents —NH2, may be converted to compounds of formula (IVA) in which R2a represents phenyl substituted at the 4-position with halo or —OR2b, by reaction of the compound of formula (IVC) with a compound of formula (IVD):X4—R2aa  (IVD)
wherein R2aa represents phenyl substituted at the 4-position with halo or —OR2b (with R2b as hereinbefore defined), and wherein X4 represents a suitable group such as —B(OH)2, —B(ORw)2 or —Sn(Rw)3, in which each Rw independently represents a C1-6 alkyl group, or, in the case of —B(ORw)2, the respective Rw groups may be linked together to form a 4- to 6-membered cyclic group (such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group, thereby forming e.g. a pinacolato boronate group), and wherein the coupling reaction may be performed in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, CuI, Pd/C, Pd(OAc)2, Pd(Ph3P)2Cl2, Pd(Ph3P)4, Pd2(dba)3 and/or NiCl2 (preferred catalysts include palladium) and a ligand such as PdCl2(dppf).DCM, t-Bu3P or the like, optionally in the presence of a suitable base (e.g. a carbonate base, hydroxide base, etc) and a suitable solvent.
Where, e.g. for compounds of formula (IVA) as defined above in which X2 represents —NH2 (or a protected derivative thereof) and R2a represents phenyl substituted at the 4-positon by halo or —OH, then conversion to the compound of formula (IV) may be possible by a coupling reaction with X4-phenyl-O-phenyl or X4-phenyl, for instance using similar catalytic coupling reactions to those mentioned above.
Hence, ultimately compounds of formula (IV) may be prepared according to the processes mentioned above.
The processes discussed above (including those to prepare compounds of formula (IV) and (IVA)) are also embraced by the concept of the invention, and are also processes that may be referred to herein as a “process of the invention”.
There is therefore provided a process for the preparation of a compound of formula (IV) which process comprises a process for the preparation of a compound of formula (I) as hereinbefore defined followed by a process for the conversion of (I) to (IV) as hereinbefore described.
There is also provided a process for the preparation of a compound (IV) or (IVA), which process comprises reaction of a compound of formula (I) (as hereinbefore defined) with a formamidine salt defined at (ii) above. Such a process is also an aspect of the invention and has associated advantages compared with reaction with formamide. For instance, the use of the formamidine salt may be advantageous as it circumvents the use of formamide, the latter being using in prior processes at high temperatures (e.g. at about 165° C., which represents a thermal hazard), whereas the use of the formamidine salt allows lower temperatures to be employed.
This aspect of the invention (conversion of compound (I) to compound (IV) or (IVA)) is preferably performed by reaction of the compound (I) with a formamidine salt (as defined hereinbefore). The formamidine salt is preferably an acetate salt and is preferably employed in excess compared with the molar equivalents of compound of formula (I) employed (e.g. in greater than two equivalents compared to compound of formula (I), e.g. greater than five equivalents, such as greater than 10 equivalents and preferably about fifteen equivalents).
This aspect of the process of the invention may be performed in the presence of a suitable solvent, which may be selected from aromatic solvents (e.g. toluene), alcohols, ethers and N-methyl-2-pyrrolidone, or the like. Glycols ethers may be particularly preferred (e.g. due to high boiling points), and a particularly preferred solvent is therefore ethylene glycol monoethyl ether. The solvent is preferably de-gassed and the reaction is preferably carried out under an inert atmosphere. More than five volume equivalents of solvent is employed (e.g. more than ten, and preferably around 13).
The resultant reaction mixture is then preferably heated to above room temperature, e.g. to above 40° C., e.g. above 60° C. such as above 80° C. Most preferably it is heated to above 100° C. However, the temperature of the reaction mixture is preferably below 160° C., for instance the preferred temperature range is between 100° C. and 140° C., most preferably between about 110° C. and 130° C. (e.g. about 120° C.).
The reaction mixture may be monitored for progress, consequently affecting the time period of the reaction. After adequate completion of the reaction, mixture may be allowed to cool down and the reaction mixture worked up to provided the desired compound.
There is further provided a process for the preparation of a compound of formula (III) as hereinbefore defined, which process comprises resolution of a corresponding racemic mixture (or derivative, e.g. protected derivative, thereof), which may be performed by means of chiral chromatography (e.g. using chiral SFC), thereby advantageously obtaining a compound of formula (III) in greater than 50% ee, for example greater than 60% ee. Given that the process of the invention is stereoselective, it is possible to purify downstream so as to provide an enantiomerically pure downstream compound.
Advantageously, this may produce product (compound (III)) in greater than 50% ee, for instance greater than 60% ee. Introducing the chirality at this stage allows the processes hereinbefore described to be effected, thereby circumventing other methods for introducing the chirality (e.g. using chiral 3-hydroxy-piperidine) and circumventing the undesired Mitsunobu reaction prior disclosed in a process for preparing ibrutinib.
Compounds of formula (III), or protected derivatives thereof may be prepared by reaction of a compound of formula (VI),

or a derivative thereof, wherein R1 is as hereinbefore defined, with a compound of formula (VII),R2—N(H)—NH2  (VII)
wherein R2 is hydrogen or a suitable nitrogen protecting group (which may be subsequently removed),
which may also be referred to as an aspect of the invention. This aspect of the invention may be conducted under standard dehydration reaction conditions optionally in the presence of a suitable solvent.
In general, the protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is described in “Protective Groups in Organic Chemistry”, edited by J. W. F. McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999).
The following scheme (which may have its individual numbering, as may the experimental section) provides a non-limiting example of various processes of the invention:

For instance, for compounds of formula (II) in which X1 represents an alkoxy leaving group —OR3a (or sulfonate), then such a compound may be prepared by alkylation (e.g. methylation) (or appropriate sulfonylation) of a compound corresponding to a compound of formula (II) but in which —OR3a represents —OH. Conversion of the —OH to other suitable leaving groups (e.g. to halo) may also be effected.
Compounds corresponding to formula (II) but in which —OR3a represents —OH may be prepared by reaction of a compound of formula (VIII),R2a—C(O)X1a  (VIII)
wherein X1a represents a suitable leaving group (e.g. chloro) and R2a is as hereinbefore defined, with a compound of formula (IX),NC—CH2—R1a  (IX)
wherein R1a is as hereinbefore defined, under suitable reaction conditions.
Some compounds described herein may be novel themselves, and hence in a further aspect of the invention, there is provided:                a compound of formula (I) or a derivative thereof        a compound of formula (III) or a derivative thereof, for instance in at least greater than 50% ee        a compound of formula (II), (IV) or (IVA) or a derivative thereof.        
In an embodiment of the invention, there is provided a process for the preparation of ibrutinib:

which process comprises a process as defined herein, followed by conversion to ibrutinib, for example:                a process for the preparation of a compound of formula (I) as herein described, followed by conversion to ibrutinib        a process for the preparation of a compound of formula (IV) or (IVA) as herein described, followed by conversion to ibrutinib, for example by deprotection (i.e. removal of the R1 group) followed by acylation with acryl chloride        a process for the preparation of a compound of formula (III) as hereinbefore described, followed by conversion to ibrutinib, for example in accordance with the procedures described herein        
Hence, there is also provided the use of certain compounds (e.g. the use of a compound of formula (I), (IV), (IVA) and/or (III)) as intermediates in the preparation of ibrutinib.
There is then further provided a process for the preparation of a pharmaceutical formulation comprising ibrutinib, which process comprises bringing into association ibrutinib (or a pharmaceutically acceptable salt thereof), which is prepared in accordance with the processes described hereinbefore, with (a) pharmaceutically acceptable excipient(s), adjuvant(s), diluents(s) and/or carrier(s).
In general, the processes described herein, may have the advantage that the compounds prepared may be produced in a manner that utilises fewer reagents and/or solvents, and/or requires fewer reaction steps (e.g. distinct/separate reaction steps) compared to processes disclosed in the prior art.
The process of the invention may also have the advantage that the compound(s) prepared is/are produced in higher yield, in higher purity, in higher selectivity (e.g. higher regioselectivity), in less time, in a more convenient (i.e. easy to handle) form, from more convenient (i.e. easy to handle) precursors, at a lower cost and/or with less usage and/or wastage of materials (including reagents and solvents) compared to the procedures disclosed in the prior art. Furthermore, there may be several environmental benefits of the process of the invention.